This invention relates to certain benzofurans having diuretic-saluretic, uricosuric and antihypertensive pharmacological activity. Further, this invention relates to processes for the preparation of such compounds; pharmacological compositions comprising such compounds; and to methods of treatment comprising administering such compounds and compositions to patients (both human and animal) for the alleviation of symptoms associated with electrolyte imbalance and fluid retention such as edema associated with hypertension.
The compounds of this invention may be represented by the following generic structure: ##STR1## wherein X is halo (chloro, fluoro, bromo or iodo), methyl or hydrogen;
Y is halo (chloro, fluoro, bromo or iodo) or methyl; PA1 X and Y can be joined to form a hydrocarbylene chain containing from 3 to 4 carbon atoms for example: 1,3-butadienylene; PA1 R is aryl such as phenyl or mono or disubstituted phenyl wherein the substituent is halo, methyl, trifluoromethyl or methoxy; aralkyl such as benzyl or mono or dinuclear substituted aralkyl wherein the substituent is halo, methyl, methoxy or trifluoromethyl, or a heterocyclic group such as a 5 or 6 membered heterocyclic ring containing one or more atoms of oxygen, sulfur or nitrogen such as 3- or 2-thienyl, 3 or 2-furyl, 1,2,5-thiadiazolyl or substituted heterocyclics as above wherein the substituent is halo or methyl. PA1 Y is chloro, and PA1 R is as defined for the more preferred benzofurans above, and the pharmacologically acceptable salts, ester and amide derivatives thereof.
Also within the scope of the present invention are the pharmaceutically acceptable salt, ester and amide derivatives of the above described compounds.
For convenience, these compounds will be collectively referred to as "dihydrobenzofuran acids."
The pharmacological studies show that the instant products are effective diuretic, saluretic and uricosuric agents which can be used in the treatment of conditions associated with electrolyte and fluid retention in the treatment of hypertension. These compounds are able to maintain the uric acid concentration in the body at pretreatment levels or to even effect a decrease in the uric acid concentration when administered in therapeutic dosages in conventional vehicles.
Many of the presently available diuretics and saluretics have a tendency upon administration to induce hyperuricemia which may precipitate uric acid or sodium urate or both in the body which may cause from mild to severe cases of gout. The instant compounds of this invention now provide an effective tool to treat those patients (which includes humans and animals) requiring diuretic and saluretic treatment without incurring the risk of inducing gout. In fact, when used in appropriate doses, the compounds of this invention function as uricosuric agents.
The preferred benzofurans of the present invention are those compounds of Formula I wherein X is halo, preferably chloro, or methyl and Y is halo, preferably chloro, or methyl, and the pharmaceutically acceptable salts, ester and amide derivatives thereof.
More preferred benzofurans of the present invention are those preferred compounds of Formula I wherein R is ##STR2## and X and Y are as defined above.
Still more preferred benzofurans of the present invention are those compounds of Formula II below: ##STR3## wherein X is chloro and
A still more preferred aspect of the invention are those compounds of Formula II wherein X and Y are both chloro and R is ##STR4## and the pharmaceutically acceptable salts, ester and amide derivatives thereof.
Several examples of specific compounds of this invention are
6,7-dichloro-2,3-dihydro-5-[hydroxy-(2-thienyl)-methyl]benzofuran-2-carboxy lic acid;
6,7-dichloro-2,3-dihydro-5-[hydroxy-(2-furyl)-methyl]benzofuran-2-carboxyli c acid;
6,7-dichloro-2,3-dihydro-5-hydroxy-[3-(1,2,5-thiadiazolyl)]methyl benzofuran-2-carboxylic acid;
6,7-dichloro-2,3-dihydro-5-(.alpha.-hydroxy-4-methoxybenzyl)benzofuran-2-ca rboxylic acid;
6,7-dichloro-2,3-dihydro-5-[(1-hydroxy-2-phenyl)-ethyl]benzofuran-2-carboxy lic acid.
The preferred groups of compounds depicted above have especially good diuretic, saluretic, uricosuric and antihypertensive pharmacological activity.
The benzofurans of the present invention may be prepared essentially by the Reaction scheme shown below: ##STR5## wherein X, Y and R are as defined, Z is halo and R.sup.2 is lower alkyl (C.sub.1-4) and M is an alkali metal cation.
In this reaction scheme, a 2,3-disubstituted-phenol (III) is treated with allyl bromide to yield the corresponding allyl ether (V). Typically the allyl bromide is employed in excess; in fact it may serve as the reaction solvent. Other solvents, provided they are compatible with the desired course of reaction may be employed, for example, ethanol, dimethylformamide and the like. Typically the reaction is conducted in the presence of a base such as sodium alkoxide, potassium carbonate and the like at a temperature in the range of from about 25.degree. to about 100.degree. C. and is substantially complete in from about 0.5 to about 2 hours. The Claisen rearrangement to obtain the 4-allyl compound (Formula VI) is effected by heating the reaction mixture at from about 100.degree. to 220.degree. C. The benzofuran nucleus (VIII) is obtained from the 4-allyl compound (VI) by treatment with a peracid such as m-chloroperbenzoic, peracetic acid and the like in a solvent such as methylene chloride, chloroform, acetic acid and the like at a temperature of from about 0.degree. C. to the reflux temperature of the solvent wherein the epoxide (VII) which is initially formed cyclizes to (VIII). There are brackets around the epoxide of Formula (VII) to indicate that it is most generally not isolated and is an intermediate in this particular reaction step. Oxidation of the resulting hydroxymethyl-substituted-benzofuran (VIII) yields the benzofurancarboxylic acid (IX).
Typically this oxidation is effected by oxidizing agents such as chromic acid, potassium permanganate and the like; the temperature of the reaction being typically in the range of from about 0.degree. C. to the reflux temperature of the solvent which is used.
The solvent can be any inert solvent that is not effected by the reaction.
Finally the benzofurancarboxylic acid compound (Formula IX) is converted to the dihydrobenzofurancarboxylic acid compounds of the instant invention (Formula I) by reacting said compound Formula (IX) or its lower alkyl (C.sub.1-4) ester (X) under Friedel-Crafts conditions with a carboxylic acid halide of the formula: RCOZ wherein R has been previously defined and Z is halogen such as chloro or bromo, to yield the desired product directly or by hydrolysis of the resultant ester (XI). The lower alkyl ester (X) can be prepared from the acid (IX) by known esterification procedures. Suitable catalysts for the Friedel-Crafts type reaction on compounds of Formula (IX) are aluminum chloride, tin (IV) tetrachloride and the like. The reaction solvent and temperature are not critical inasmuch as any solvent which is inert to the acyl halide/benzofuran reactants may be employed. In this regard, suitable solvents include aliphatic and cycloaliphatic hydrocarbons such as heptane, cyclohexane, and the like; nitrohydrocarbons such as nitrobenzene and the like; and halogenated hydrocarbons such as carbon tetrachloride, methylene chloride, and the like are employable. The reaction is generally run until formation of the desired product (I) is complete, preferably from about 1 to 6 hours.
Typically the reaction is conducted from 0.degree. C. to the reflux temperature of the particular solvent employed but temperatures up to about 100.degree. maximum may be employed. Applicants have found that a better yield of final product (I) is obtained from compound (IX) by using no inert solvent but using a slight excess of the acyl halide.
Finally, in order to convert the dihydrobenzofurancarboxylic acid compound (XII) to the 5-[hydroxy(substituted)-methyl]-2,3-dihydrobenzofuran-2-carboxylic acid compounds of the instant invention (Formula I), Compound XII is reduced to an intermediate compound (XIII) which is then acidified to the desired product (Formula I). The reduction and acidification can and usually are carried out in the same vessel.
The reduction step is carried out by reacting Compound XII with a reducing agent which selectively reduces the carbonyls to alcohols when there is a carboxylic acid present. A preferable reducing agent is MBH.sub.4 where M is an alkali metal cation such as particularly sodium borohydride or potassium borohydride.
The reduction is carried out in the presence of a solvent such as water or an alcohol. The use of a particular solvent is however not critical to the reaction.
The reduction is generally carried out anywhere from 1-24 hours and at a temperture of from 0.degree. - 50.degree. C. but preferably at ambient temperature.
The product (I) is then isolated from the reaction mixture where Compound (XIII) is formed as an intermediate by acidifying said reaction mixture with an inorganic acid such as an inorganic mineral acid as hydrochloric or sulfuric acid to precipitate the product (I) which is then isolated by filtration.
As previously mentioned, the nontoxic, pharmacologically acceptable salts of the acids of Formula (I) and (II) are within the scope of this invention. These salts include those of alkali metals, alkaline earth metals and amines such as ammonia, primary and secondary amines and quaternary ammonium hydroxides. Especially preferred metal cations are those derived from alkali metals, e.g., sodium, potassium, lithium, and the like and alkaline earth metals, e.g., calcium, magnesium, and the like and other metals, e.g., aluminum, iron and zinc.
Pharmaceutically acceptable salts can be formed from ammonia, primary, secondary, or tertiary amines, or quaternary ammonium hydroxides such as methylamine, dimethylamine, trimethylamine, ethylamine, N-methylhexylamine, benzylamine, .alpha.-phenethylamine, ethylenediamine, piperidine, 1-methylpiperazine, morpholine, pyrrolidine, 1,4-dimethylpiperazine, ethanolamine, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-methylglucamine, N-methylglucosamine, ephedrine, procaine, teramethylammonium hydroxide, tetraethylammonium hydroxide, benzyltrimethylammonium and the like. These salts are particularly useful as parenteral solutions because they are very soluble in pharmaceutical carriers such as water or alcohol.
Also included within the scope of this invention are the ester and amide derivatives of the instant products which are prepared by conventional methods well known to those skilled in the art. Thus, for example, the ester derivative may be prepared by the reaction of an dihydrobenzofuran-2-carboxylic acid of this invention with an alcohol, for example, with a lower alkanol such as methanol or ethanol. The amide derivatives may be prepared by converting the same acid to its corresponding acid chloride by treatment with thionyl chloride followed by treating said acid chloride with ammonia, an appropriate mono-lower alkylamine, di-lower alkyl amine or a hetero amine, such as piperidine, morpholine and the like, to produce the corresponding amide compound. These and other equivalent methods for the preparation of the ester and amide derivatives of the instant products will be apparent to one having ordinary skill in the art and to the extent that said derivatives are both non-toxic and physiologically acceptable to the body system, said derivatives are the functional equivalent of the corresponding free acids of the present invention.
Of the non-toxic pharmaceutically acceptable salt, ester and amide derivatives of Formulae I and II, the preferred salts are those of ammonia, amines and of the alkali metals -- principally sodium and potassium; the preferred esters are those derived from lower alkanols having from 1 to about 6 carbon atoms; the preferred amides are those derived from mono- and di-lower alkyl amines and hetero amines such as piperidine, morpholine and the like.
Although diuretics are often life-saving because of the above beneficial therapeutic effects, most of them have the disadvantage of causing the excretion of appreciable amounts of potassium ions. When an excessive loss of potassium ions occurs, a severe muscular weakness and feeling of extreme physical exhaustion results. The patient eliminates the unwanted sodium ions due to the action of the diuretic drugs but the undesired elimination of the potassium ions produces an imbalance that should not be allowed to persist.
This invention also involves co-administration of a dihydrobenzofurancarboxylic acid with a pyrazinoylguanidine either in the form of a salt and/or as a mixture with a hydrochloride salts of pyrazinoylguanidine, to thereby prevent the elimination of excessive amounts of potassium ions without altering or actually increasing the amount of sodium ions that are eliminated.
To achieve the beneficial results of this invention, the preferred pyrazinoylguanidine compound is N-amidino-3,5-diamino-6-chloropyrazinecarboxamide (amiloride) or its hydrochloride salt (amiloride hydrochloride) which is described in the literature and patented arts.
Another advantage of the N-amidino-3,5-diamino-6-chloropyrazinecarboxamide salts of the dihydrobenzofurancarboxylic acid diuretics is their insolubility which makes the salts' gastrointestinal absorption slower and more gradual providing a chemical method of achieving the same effect as microencapsulation.
The examples which follow illustrate the benzofuran products of the present invention and the methods by which they are prepared. However, the examples are illustrative only and it will be apparent to those having ordinary skill in the art that all the products embraced by the above-given description of the present invention may also be prepared in an analogous manner by substituting the appropriate starting materials for those set forth in the examples.